Although classical immune complex-mediated pathogenesis is an important mediator of SLE, recent data suggest that SLE pathogenesis is more complicated, with T cells also playing effector roles in addition to promoting autoantibody production. However, relatively little is known about the autoantigens (autoAgs) that drive these T cells, in either secondary lymphoid organs or within tissues in which T cells promote inflammation. We and others have shown that B cells play a critical role in presenting autoantigens to T cells. These T-B interactions are essential for autoimmunity, and we believe they represent a potential target for disease modulation. Thus, a major long-term goal of our laboratory is to understand the nature of these interactions in the induction and maintenance of systemic autoimmunity. In the current proposal, we follow up on our previous work by asking: At what stage(s) of T cell activation and expansion do B cells play a critical role? Do B cells promote T cell activation in an autoAg-specific manner, and if so, do they serve to focus the autoreactive T cell response? How are the T cells that are activated in a B-cell dependent fashion maintained and driven, once they enter tissues where they presumably contribute to the inflammatory response? In Aim 1, we will test the hypothesis that B cells are important for initiation and maintenance of disease by developing novel systems to selectively delete or inhibit mature B cells in vivo at points during the disease course. In Aim 2, we will test the hypothesis that B cells skew the autoreactive T cell repertoire and selectively expand self-reactive T cells by assaying the autoreactive T cell repertoire that develops in the presence or absence of B cells and also in mice with B cells that express either autoreactive or irrelevant specificities. In Aim 3, we will test the hypothesis that the T cells that infiltrate tissues such as skin and kidney in MRL mice include tissue-specific autoreactive T cells by assaying the reactivity of these T cells to DCs that are isolated from the same lesions (where we have found they form dense networks) vs. other DC populations and to DCs that are primed with kidney parenchymal antigens.